THE INTERFERON SYSTEM: (1) To explore further our recent discovery that defective-interfering particles of vesicular stomatitis virus (VSV) which contain covalently linked message and anti-message do not kill cells, but are exquisitely efficient inducers of interferon. We plan to determine how ubiquitous is the distribution of interferon-inducing DI particles, (2) To determine the nature of the interferon inducing moiety in virus-infected cells, (3) To determine why primary cells aged in vitro hyperproduce interferon and develop an enhanced antiviral state upon stimulation with appropriate inducers, and (4) To define the significance of interferon action in the inhibition of primary transcription in cells infected with VSV. CELL KILLING BY VIRUSES: (1) To use temperature-sensitive mutants of VSV, Sindbis and NDV, selective inhibitors of macromolecular synthesis, and viral interference per se as probes to determine the role of cellular and viral factors in cell-killing by viruses, subviral components, and dsRNA of viral and synthetic origin, (2) To test further our hypothesis that cell-killing by VSV requires functional virion-associated transcriptase (not new-transcriptase) in order to synthesize mRNAs for proteins N and NS and that they may be translated into minimally functional proteins, (3) To define the nature and mode of action of putative cell killing factor induced by VSV. CELL-SPARING: To define the role of the interferon system and CPE-suppressing particles in the prevention of cell-killing by viruses. PERSISTENT INFECTION: To define the role of interferon-inducing DI particles, ts-mutants and CPE-suppressing particles in persistent infection.